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Progress to Report on nilotinib

I’m trying hard to get back into fighting shape after a summer that left little time for it.

Have you wondered, as I have, what the progress is on any of the new “miracle treatments” for Parkinson’s? I’m not one to sit at the computer for long periods every day checking for new research. So I love it when progress comes to me, as it did last Monday at the Parkinson’s Cafe (on Pender Drive in Fairfax, but that is for another day). Our Eleanor, came up to me with some information on the drug, niloginib, an FDA-approved drug for leukemia which is being tested for possible usage with Parkinson’s patients. A tip of the hat and full acknowledgement for this article by Nancy Robertson, published and/or released by the Georgetown University Medical Center on October 17, 2015.

OCTOBER 17, 2015 – An FDA-approved drug for leukemia improved cognition, motor skills and non-motor function in patients with Parkinson’s disease and Lewy body dementia in a small clinical trial, say researchers at Georgetown University Medical Center (GUMC).

The drug, nilotinib (known as Tasigna® by Novartis) also led to statistically significant and encouraging changes in toxic proteins linked to disease progression.

The study’s findings were presented at Neuroscience 2015, the annual meeting of the Society for Neuroscience, in Chicago on Oct. 17.

Charbel Moussa, MD, PhD, who directs Georgetown’s Laboratory of Dementia and Parkinsonism, conducted the preclinical research that led to the discovery of nilotinib for the treatment of neurodegenerative diseases.

WALKING AGAIN

To conduct the clinical study, he partnered with Fernando Pagan, MD, a GUMC associate professor of neurology who directs the Movement Disorders Program at MedStar Georgetown University Hospital.

“To my knowledge, this study represents the first time a therapy appears to reverse – to a greater or lesser degree depending on stage of disease – cognitive and motor decline in patients with these neurodegenerative disorders,” says Pagan. “But it is critical to conduct larger and more comprehensive studies before determining the drug’s true impact.”

The investigators report that one individual confined to a wheelchair was able to walk again and that three others who could not speak were able to hold conversations.

Pagan notes there was no control group for comparison in the study, and that the drug was not compared with a placebo or other medications used to treat Parkinson’s.

SAFETY TEST

But the researchers report that during use of the medication by the participants, production of dopamine increased in many patients, requiring doses of L-dopa and other dopamine-sparing drugs used to treat Parkinson’s to be lowered or stopped.

“The use of nilotinib in doses much smaller than are used to treat cancer, which is up to 800 mg daily, was well tolerated with no serious side effects,” Pagan explains. “The dose used in this study was 150 and 300 mg daily.”

The researchers also found that the drug penetrates the blood-brain barrier in amounts greater than dopamine drugs.

The observed efficacy in cognition, motor skills and non-motor function improvement (such as constipation) for many patients was the most dramatic result, Pagan notes.

“Study participants with earlier stage disease responded best, as did those diagnosed with Lewy body dementia, often described as a combination of Parkinson’s and Alzheimer’s diseases,” he says.

LIFE-CHANGING IMPROVEMENT

Alan Hoffman, a professor emeritus of social science education at Georgia State University, was diagnosed with Parkinson’s disease in 1997. He says he participated in several clinical trials with no benefit until he enrolled in Pagan’s study.

“Before the nilotinib, I did almost nothing around the house,” he says. “Now, I empty the garbage, unload the dishwasher, load the washer and the dryer, set the table, even take responsibility for grilling.”

In the three weeks prior to enrolling in the study, Hoffman says he fell eight times, but he only fell once during six months on the study. His speech has improved, as has his thinking.

“My wife says it’s life-changing for her and for my children and grandchildren,” Hoffman says. “To say that nilotinib has made a change in our lives is a huge understatement.”

TRANSLATIONAL SUCCESS

Moussa, an inventor on a Georgetown University patent application for nilotinib and other similar drugs for neurodegenerative diseases, notes that the research went to clinical trials only two years after his initial discovery.

He first set out to find approved cancer drugs that could penetrate the blood-brain barrier and turn on the “garbage disposal machinery” inside neurons to clear toxic intracellular proteins and prevent their accumulation within, or secretion outside of, brain cells.

“A lot of institutions talk about expediting the translation of research from the lab to the bedside, but it doesn’t happen quickly very often,” Moussa says. “This is a solid example of how that is possible and why it is so important.”

PATIENTS CONTINUE TREATMENT

Hoffman and other patients in the clinical trial can continue taking nilotinib as part of an expanded access study. Georgetown researchers are now planning larger clinical trials with nilotinib for patients with Parkinson’s and other similar diseases including Alzheimer’s disease, likely to begin in 2016.

The phase I study received philanthropic funding and was supported by the Georgetown-Howard Universities Center for Clinical and Translational Science.

Co-authors of the study represent the MedStar Georgetown Movement Disorders Program, GUMC’s Translational Neurotherapeutics Program and the Laboratory for Dementia and Parkinsonism, and the Georgetown-Howard Universities Center for Clinical and Translational Science Clinical Research Unit.

This got me excited to see what else is happening with the testing of this drug. I found another Georgetown University Medical Center article updating the progress just a few weeks ago on July 11th. Written by Karen Teber, it is entitled, ” STUDY: CANCER DRUG RESTORES BRAIN DOPAMINE, REDUCES TOXIC PROTEINS IN PARKINSON, DEMENTIA

WASHINGTON (July 11, 2016) — A small phase I study provides molecular evidence that an FDA-approved drug for leukemia significantly increased brain dopamine and reduced toxic proteins linked to disease progression in patients with Parkinson’s disease or dementia with Lewy bodies. Dopamine is the brain chemical (neurotransmitter) lost as a result of death of dopamine-producing neurons in these neurodegenerative diseases.

Researchers from Georgetown University Medical Center (GUMC), say the findings, described in the Journal of Parkinson’s Disease, support improved clinical outcomes observed and first reported at the Society for Neuroscience annual meeting in October 2015.

The study tested nilotinib taken daily for six months. A much smaller dose of nilotinib (150 or 300 mg once daily) was used compared to the dose for chronic myelogenous leukemia (300-400 mg twice daily). Twelve patients were enrolled in the clinical trial — one patient withdrew due to an adverse event. Researchers say the drug appears to be safe and well tolerated in the remaining 11 participants who completed the study.

In addition to safety, the researchers also examined biological markers in the blood and cerebral spinal fluid as well as cognitive, motor and non-motor improvement. They found significant signs that nilotinib may provide benefit for patients with these neurodegenerative diseases.

“These results need to be viewed with caution and further validated in larger placebo controlled trials, because this study was small, the patients were very different from each other, and there was no placebo,” says the study’s senior investigator, Charbel Moussa, MD, PhD, scientific and clinical research director of the GUMC Translational Neurotherapeutics Program (pictured right).

Among the biomarker findings were that:

The level of the dopamine metabolite homovanillic acid — an indicator that dopamine is being produced — steadily doubled, even with the loss of most dopamine neurons. Most study participants were able to stop using, or reduce their use of, dopamine replacement therapies;
The level of the Parkinson’s related oxidative stress marker DJ-1 — an indicator that dopamine-producing neurons are dying — was reduced more than 50 percent after niltonib treatment; and
The levels of cell death markers (NSE, S100B and tau) were significantly reduced in cerebrospinal fluid (CSF) suggesting reduced neuronal cell death.
In addition, Moussa adds that it appears nilotinib attenuated the loss of CSF alpha-synuclein, a toxic protein that accumulates within neurons, resulting in reduced CSF levels in both Parkinson’s disease and dementia with Lewy bodies.

The researchers also said that all 11 patients who tolerated the drug reported meaningful clinical improvements. All patients were at mid-advanced stages of Parkinsonism and they all had mild to severe cognitive impairment.

“Patients progressively improved in motor and cognitive functions as long as they were on the drug — despite the decreased use of dopamine replacement therapies in those participants with Parkinson’s and dementia with Lewy bodies,” says the study’s lead author, Fernando Pagan, MD, medical director of the GUMC Translational Neurotherpeutics Program and director of the Movement Disorders Program at MedStar Georgetown University Hospital (pictured left).

But three months after withdrawal of the drug, participants returned to the same reduced cognitive and motor state they had before the study began, Pagan adds.

Some serious side effects were reported including one patient who withdrew at week four of treatment due to heart attack and three incidents of urinary tract infection or pneumonia. The researchers say these incidents are not uncommon in this patient population, and additional studies are needed to determine if the adverse events are related to use of nilotinib.

“Long term safety of nilotinib is a priority, so it is important that further studies be conducted to determine the safest and most effective dose in Parkinson’s, says Pagan.

The researchers designed the clinical trial to translate several notable observations in the laboratory. The preclinical studies, led by Moussa, showed that nilotinib, a tyrosine kinase inhibitor, effectively penetrates the blood-brain barrier and destroys toxic proteins that build up in Parkinson’s disease and dementia by turning on the “garbage disposal machinery” inside neurons.

Their published studies also showed nilotinib increases the levels of the dopamine neurotransmitter — the chemical lost as a result of neuronal destruction due to toxic protein accumulation — and improves motor and cognitive outcomes in Parkinson’s and Alzheimer’s disease animal models.

“Our hope is to clarify the benefits of nilotinib to patients in a much larger and well controlled study. This was a very promising start,” Moussa says. “If these data hold out in further studies, nilotinib would be the most important treatment for Parkinsonism since the discovery of Levodopa almost 50 years ago.”

He adds, “Additionally, if we can validate nilotinib effects on cognition in upcoming larger and placebo controlled trials, this drug could become one of the first treatments for dementia with Lewy bodies, which has no cure, and possibly other dementias.”

Two randomized, placebo-controlled phase II clinical trials are planned for summer/fall in Parkinson’s and Alzheimer’s diseases. The Translational Neurotherpeutics Program is also planning a small trial in ALS (Lou Gherig’s disease).

According to Novartis, the cost (as of Oct. 2015) of nilotinib for the treatment of CML was about $10,360 a month for 800 mg daily. The dose used in this study was lower — 150 and 300 mg daily.

The phase I study received philanthropic funding and was supported by the Georgetown-Howard Universities Center for Clinical and Translational Science.

Moussa is listed as an inventor on a patent application that Georgetown University filed related to the use of nilotinib and other tyrosine kinase inhibitors for the treatment of neurodegenerative diseases.

The researchers represent the MedStar Georgetown Movement Disorders Program, GUMC’s Translational Neurotherapeutics Program, the Laboratory for Dementia and Parkinsonism, the Georgetown-Howard Universities Center for Clinical and Translational Science Clinical Research and the department of biostatistics.

About Georgetown University Medical Center
Georgetown University Medical Center (GUMC) is an internationally recognized academic medical center with a three-part mission of research, teaching and patient care (through MedStar Health). GUMC’s mission is carried out with a strong emphasis on public service and a dedication to the Catholic, Jesuit principle of cura personalis — or “care of the whole person.” The Medical Center includes the School of Medicine and the School of Nursing & Health Studies, both nationally ranked; Georgetown Lombardi Comprehensive Cancer Center, designated as a comprehensive cancer center by the National Cancer Institute; and the Biomedical Graduate Research Organization, which accounts for the majority of externally funded research at GUMC including a Clinical and Translational Science Award (UL1TR001409-01) from the National Institutes of Health.

If, like me, you find this interesting , there is a way to sign up to receive updates on the GUMC website. Try this link.

What do you see out on the horizon? What makes you feel the most hopeful?

As for the Parkinson’s Cafe, it is a drop-in program from 10am-noon held at the Insight Memory Care Center at 3953 Pender Drive in Fairfax. There’ve been 3 so far and each one seems to have developed its own purpose or format based on who shows up. The next Parkinson’s Cafe will be held on the second Monday of September. For more information check out the Parkinson’s Cafe website..

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"I AM"- are the two most powerful words in the dictionary because the ending determines your destiny....so join me in my fight against PD to make sure that everyone who suffers from this chronic progressive degenerative disease can develop the courage to shout to the wind- I AM Fierce and Courageous ....